SOLUBILITY It can be defined quantitatively as the conc. of solute in a saturated solution at a certain temperature, and qualitatively as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion It can also be defined as the molecular dispersion of solute in the solvent. Importance of solubility: It is an important physico-chemical property of the drug, It is an important parameter to achieve desired concentration in systemic circulation . Solubility behavior of the drug is a one of the important aspects of preformulation testing for poorly soluble drug
EXPRESSION FOR APPROXIMATESOLUBILITYDescriptive terms Relative amounts of solvents to dissolve 1 part of soluteVery soluble Less than 1Freely soluble From 1-10Soluble From 10-30Sparingly soluble From 30-100Slightly soluble From 100-1000Very slightly soluble From 1000-10,000Insoluble or practically More than 10,000insoluble
PROBLEMS WITH POOR SOLUBILITY: Reduced drug efficiency Reduced absorption of drug May cause side effects
SOLUBILIZATION It can be defined as the preparation of a thermodynamically stable isotropic solution of a substance normally insoluble or very slightly soluble in a given solvent by the addition of component or components or by any suitable methods
PROCESS OFSOLUBILIZATION1) Breaking of inter-ionic or inter–molecular bonds in the solute2) Separation of solute molecules to provide space for the solute3) Interaction between the solvent and solute molecule or iona) Molecules of solids break away from bulkb) Separation of solvent moleculesc) Freed solid molecules is integrated into the holes of solvent molecule
SOLUBILIZATION TECHNIQUES- CO- SOLVENCY Substances like weak electrolytes and non-polar molecules are poorly soluble in water . The solubility of these substances can be enhanced by the addition of water miscible solvents in which the drug has good solubility. This process of improving solubility is called as co-solvency and the solvents used are known as co-solvents. This technique is mainly used in the formulation of parenterals. Commonly used co-solvents are Ethanol, Sorbitol, Glycerin, Polyethylene glycol, propylene glycol etc. The solubilizing effect by co-solvency is depends on the polarity of the drug with respect to solvent and co-solvent. That means more non-polar the solute the greater is the solubilization achieved by the added solvents
• Mechanism responsible for solubility enhancementthrough co-solvency is by reducing the interfacial tensionthe predominantly aqueous solution and hydrophobicsolutes and reduces the contact angle between the solid andliquid• Co-solvents increases the solubility by reducing thedifference between the polarity of the drug and watersustemEx. For co-solvencyThe solubility of diazepam can be increased by using 10%ethanol and 40% propylene glycol. Phenobarbitone is relatively insoluble in water but itsolubility can be increased by using mixture of solventslike water, alcohol and glycerin
ADDITION OF SURFACTANTS Surfactants are very useful as absorption enhancers and enhance both dissolution rate as well as permeability of the drug . Surfactants act by reducing the surface tension and forms colloidal aggregates known as micelles. Micelles are formed at CMC . Ability of a surfactant solution to dissolve or solubilise water insoluble materials starts at CMC and increases with increase in conc. of micelles . Lipophilic surfactants with HLB value higher than 15 are best solubilising agents Concentration of surfactant must be controlled very less conc. Improper solubilization very high conc. Affect on bioavailability
SOLID DISPERSION TECHNIQUE It is the dispersion of one or more active ingredients in an inert carrier or matrix in solid state prepared by fusion or melting-solvent method. It is the dispersion of a drug or drugs in solid diluent or diluents. Solid dispersions may also be called “ solid state dispersions”. Solid dispersion provides particle size reduction and increased rates of dissolution Various systems of solid dispersions:1) Simple eutectic mixtures2) Solid solutions3) Glass solution and glass suspension4) Amorphous precipitation of drug in crystalline carrier5) Compound or complex formation between drug and carrier6) Any combination among the above
COMPLEXATION It is reversible association of a substrate and ligand molecule. The most common complexing ligands are cyclodextrins, caffeine, urea, polyethylene glycol, N methylglucamide. cyclodextrin are unique since they increase the water solubility of poorly soluble drugs by fitting them into the hydrophobic cavity of the cyclodextrin molecule. These cyclodextrins have the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility.
CHANGING TEMPERATURE The solubility of a solute or solid in a liquid is dependent on temperature, nature of solute and nature of solvent ∆Hs( heat of solution) represents the heat released or absorbed when a mole of solute is dissolved in a large amount of solvent If the solution process is endothermic, increase in temperature increases the solubility of the solute And if the solution process is exothermic, increase in temperature decreases the solubility of the solute
HYDROTROPHY Addition of large amount of a second solute results in an increase in the aqueous solubility of another solute. Concentrated aqueous hydrotropic solutions of sodium benzoate, sodium salicylate, urea, nicotinamide, sodium citrate and sodium acetate have been observed to enhance the aqueous solubilities of many poorly water-soluble drugs. Advantages:1. Hydrotropy is suggested to be superior to other Solubilization method, such as miscibility, micellar Solubilization, cosolvency and salting in, because the solvent character is independent of pH, has high selectivity and does not require emulsification2. It only requires mixing the drug with the hydrotrope in water.3. It does not require chemical modification of hydrophobic drugs, use of organic solvents, or preparation of emulsion system
SOLID STATE MANIPULATIONS Polymorphic modifications Solubility of each form depends upon the ability of the molecules to escape from the crystal to solvent. The stable form posses the lower free energy at a particular temperature and therefore has the lower solubility or escaping tendency where as the meta stable forms posses higher free energy hence has higher solubility. About fifty to hundred percent increase in the dissolution rate can be achieved through polymorphic modifications.Examples: Chloramphenicol palmitate (form B) Methyl prednisolone (form 2) Chlor tetracycline (form B)
NON CRYSTALLINE SOLUTES (AMORPHOUS)As the term implies they will not contain internal crystal lattice structure. These are thermodynamically unstable. Amorphous solid forms give faster dissolution rates and higher solubility than polymorphic modifications.Eg : NovobiocinThus, the order for dissolution of different solid forms of drug isAmorphous > Metastable >Stable
SOLVATES (PSEUDO POLYMORPHISM ) The recrystallization of many drug substances from solution will results in the formation of solids containing solvent molecules as an integral part of their crystal structure. Majority of these crystalline materials referred as pseudo polymorphs, contain stoichiometric amount of solvent. Anhydrates > hydrates Organic solvates > organic non-solvatesEnhances the solubility of drug markedly.Examples: Pentanol solvates of fludrocortisone Chloroform solvates of griseofulvin Cephalexin hydrate
Salt formation Salts have improved solubility and dissolutioncharacteristics in comparison to the original drug. Alkalimetal salts of acidic drugs like penicillin and strong acidsalts of basic drugs like atropine are water-soluble thanthe parent drug.Precipitation:In this method, the poorly aqueous soluble drug isdissolved in a suitable organic solvent followed by itsrapid mixing with a non-solvent to effect precipitation ofdrug in nano size particles. The product so prepared isalso called as hydrosol. Ex. Cyclosporine
Other techniques•Micronization•Nanonisation• Supercritical Fluid Recrystallization• Spray freezing into liquid and lyophilization•Evaporative precipitation into aqueous solution•Use of precipitation inhibitors•Selective Adsorption on Insoluble Carriers•Solvent Deposition• Drug derivatisation
ConclusionThe aqueous solubility of drug is often a limitingfactor in developing most desirable dosage form.A highly solubilized formulation is highly desiredto minimize dissolution limited absorption .Often,these early stage formulations become thebackbone for the later stage commercialformulations. But still there has been a lot ofresearch going on in this topic and many newerand advanced methods are used to enhance thesolubility of the drug.
A particular slide catching your eye?
Clipping is a handy way to collect important slides you want to go back to later.